Transition‐Metal‐Free Tunable Chemoselective N Functionalization of Indoles with Ynamides

Abstract

Two unprecedented N functionalizations of indoles with ynamides are described. By varying the electron‐withdrawing group on the ynamide nitrogen atom, either Z‐indolo‐etheneamides or indolo‐amidines can be selectively obtained under the same metal‐free reaction conditions. The scope and synthetic potential of these reactions, as well as some mechanistic insights provided by DFT calculations, are reported.

Ketenimines Generated from Ynamides: Versatile Building Blocks for Nitrogen‐Containing Scaffolds

“…[19] Using sodium tert-butoxide in dimethylformamide triggered thec leavage of the electron-with-drawing group to give phenylketenimine 3,p resumably throught he intermediacy of sodium indolide as the nucleophile. [19] Using sodium tert-butoxide in dimethylformamide triggered thec leavage of the electron-with-drawing group to give phenylketenimine 3,p resumably throught he intermediacy of sodium indolide as the nucleophile.…”

“…For their part, Dodd and Cariou studied the reaction between indoles andu nsubstituted ynamides 72 under basic conditions (Scheme 25). [19] Using sodium tert-butoxide in dimethylformamide triggered thec leavage of the electron-with-drawing group to give phenylketenimine 3,p resumably throught he intermediacy of sodium indolide as the nucleophile. [20] Addition of the anion to the ethenimine then led to indolic amidine 73 in good yields that vary depending on the nature of the electron-withdrawing group.…”

Base‐Mediated Generation of Ketenimines from Ynamides: Direct Access to Azetidinimines by an Imino‐Staudinger Synthesis

“…However,d irect application of our previously disclosed reaction conditions [4] -namely 1.0 equiv of ynamide, 1.0equiv of t-BuONa as base, DMF as solvent, and with molecular sieves at RT-proved to be totally ineffective, even after prolonged reaction time ( Table 1, entry 1). We reasonedt hat the cycloaddition process required thermal activation and although traditional heating (entry 2) was unsuccessful, using microwave conditions [11] allowed the reaction to take place (entry 3).…”

“…[2] We have shown that under strongly basic conditions [3] an unprecedented nucleophilic addition of various heteroarenes at the b positionc ould take place. [4] Moreover,d epending on the substitution pattern of the nitrogen atom, the same basic conditions could lead to an a-nucleophilic addition, albeit with the loss of the electron-withdrawing group (EWG). In the a-nucleophilic addition case, base activation would lead to cleavage of the EWG, forminga na mide that would eventually evolvet oward ketenimine 3.…”

“…In the a-nucleophilic addition case, base activation would lead to cleavage of the EWG, forminga na mide that would eventually evolvet oward ketenimine 3. [4,5] To further expand the potentialo fhighly reactive intermediate 3,w es ought to trap it in a[ 2 + +2] cycloaddition. [6] By analogy with the well-established Staudinger synthesis of b-lactams, [7] and based on the pioneering studies by Ghosez [8] and Regitz, [9] we envisioned that the N-phenylethenimine 3a generated in situ from ynamide 1a would be sufficiently electrophilic to react with imine 4 to ultimately give azetidinimine 5 (Scheme2).…”